Abstract

Insulin resistance contributes importantly to the pathogenesis of noninsulin-depedendent diabetes mellitus (NIDDM) (1, 2). Furthermore, in longitudinal studies, insulin resistance has been shown to be among the best predictors of future development of NIDDM (3,4). Therefore, we have focused upon genetic causes of insulin resistance in the hope that this will help us to identify genetic factors that predispose to the development of NIDDM. Because of the central role of the insulin receptor in mediating the first step in insulin action (5), we have begun by examining the insulin receptor gene in insulin resistant patients. We have selected patients who manifest an extreme degree of insulin resistance in the hope that the severe insulin resistance would be associated with major biochemical defects, thereby simplifying the task of identifying the molecular defect. In this review, we will summarize the mutations that have been identified in the insulin receptor genes of patients with extreme insulin resistance. Interestingly, multiple different types of mutations have been identified (5). In addition to elucidating the molecular genetics of human insulin resistance, these studies have begun to give new insights into structure-function relationships of the insulin receptor protein.